Synthesis method of saflufenacil

Abstract

The invention provides a synthesis method of saflufenacil, and belongs to the field of chemical synthesis. The preparation method comprises the following steps: reacting N-(2-chloro-4-fluoro-5-aminobenzoyl)-N '-isopropyl-N'-methyl sulfonamide serving as a raw material with chloroformate in a strong polar solvent, then directly adding alkali and ethyl 3-amino-4, 4, 4-trifluoro-2-butenoate into the reaction material, and carrying out cyclization reaction, so as to obtain the N-(2-chloro-4-fluoro-5-aminobenzoyl)-N '-isopropyl-N'-methyl sulfonamide. And carrying out methylation reaction on the cyclization reaction material and a methylation reagent to obtain saflufenacil. The selected reaction solvent is relatively single and easy to recover, so that the reaction operation is simple, the product yield is improved, and the method is suitable for industrial large-scale production and has a wide application prospect.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for synthesizing saflufenacil. Background Art

[0002] Safamiflu is a new uracil herbicide with wide crop applicability and excellent broadleaf weed control spectrum. It has huge weed control market potential in no-till stubble, non-arable land, orchards, beans and wheat crops.

[0003] Its unique effect lies in the "additive effect" when mixed with glyphosate. It can not only promote the absorption and conduction of glyphosate by weeds, but also cause weeds to begin to die 1 to 3 days after application, usually reducing the amount of glyphosate by 30.5%. It can also prevent and control a variety of dicotyledonous weeds that are tolerant or even resistant to glyphosate, triazine, and sulfonylurea (ALS inhibitors) herbicides; its residual activity in the soil can extend the effective period to 60 days.

[0004] The current production process of saflufenacil is:

[0005] Route 1: CN1989111B uses 4-fluoro-2-chlorobenzoic acid as a raw material to synthesize an intermediate through nitration, chlorination, ring closure and other steps (the reaction route is as follows:). The reaction has a low yield, harsh conditions and a long route. In addition, solvent switching and solid discharge occur multiple times in the later stage of the reaction, which is not suitable for industrial production.

[0006]

[0007] Route 2: CN100558714C reports the synthesis of an intermediate by the reaction of isocyanamide and trifluorocrotonamine, but the reaction conditions are harsh (conducted in a nitrogen atmosphere and using sodium hydride as a base);

[0008]

[0009] Route 3: CN100509771C adopts the following production process, but the intermediate synthesis yield is low, there are many wastes, it is dangerous, the conditions are harsh, and it is not easy to produce on a large scale;

[0010]

[0011] Route 4: CN 113979953 B uses compound II as the starting material to generate compound III-2; after hydrolysis with sulfuric acid, amination, and then reaction with N-methylisopropylaminesulfonyl chloride, compound III or compound I is generated. However, the inventors found through experiments that amide and N-methylisopropylaminesulfonyl chloride basically do not react, so this route is not suitable.

[0012]

[0013] Route 5: CN101821233B uses N-methyl-N-(1-methylethyl)aminosulfonamide and 2-chloro-4-fluoro-3-nitrobenzoyl chloride as raw materials to prepare N-(2-chloro-4-fluoro-5-nitrobenzoyl)-N′-isopropyl-N′-methylsulfonamide, and then undergoes amination, reaction with ethyl chloroformate, cyclization, and methylation to obtain benzsulfamide. During the reaction process of this process, there are multiple solvent switching and solid discharge, resulting in solvent waste, complicated three-waste treatment (three-waste treatment is involved in solvent switching or each discharge), and low yield (the total yield of the three steps is only 74%).

[0014] In summary, there is an urgent need to propose a new process method with simpler operation and higher yield. Summary of the invention

[0015] Purpose of the Invention

[0016] In order to overcome the above-mentioned shortcomings, the purpose of the present invention is to provide a method for synthesizing saflufenacil. The reaction solvent selected in the present invention is relatively single and easy to recycle, so that the reaction operation is simple, the product yield is improved, and it is suitable for industrial scale-up production and has broad application prospects.

[0017] Solution

[0018] To achieve the purpose of the present invention, the technical solution adopted by the present invention is as follows:

[0019] In a first aspect, the present invention provides a method for synthesizing saflufenacil, wherein N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide is used as a raw material to react with a chloroformate in a strong polar solvent, and then a base and 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester are directly added to the reaction material to carry out a cyclization reaction, and the cyclization reaction material is subjected to a methylation reaction with a methylating agent to obtain saflufenacil.

[0020] Further, the strong polar solvent includes one or more of N-methylpyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dipropyl ether, dipropylene glycol dimethyl ether, dipropylene glycol diethyl ether, dipropylene glycol dipropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dipropyl ether, propylene glycol dimethyl ether, propylene glycol diethyl ether, propylene glycol dipropyl ether, and polyethylene glycol 200-800; optionally, polyethylene glycol 200-800 includes one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800.

[0021] Further, the mass ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the strong polar solvent is 1:0.5-10, optionally 1:0.6-10, optionally 1:0.8-10, optionally 1:0.8-3.

[0022] Further, the molar ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to chloroformate is 1:1.0-3.0, optionally 1:1.2-1.8.

[0023] Furthermore, the chloroformate includes one or more of methyl chloroformate and ethyl chloroformate.

[0024] Further, in the reaction of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide and chloroformate, the reaction temperature is 15-130°C, optionally 80-110°C, optionally 90-100°C, optionally 95-100°C.

[0025] Further, in the cyclization reaction, the base is a strong organic base; optionally, in the cyclization reaction, the base is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydrogen, sodium amide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide.

[0026] Further, the molar ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the base is 1:1 to 10, optionally 1:1.6 to 2.5, optionally 1:2.0 to 2.5, optionally 1:1.9 to 2.2;

[0027] Furthermore, the cyclization reaction temperature is 80-200°C, optionally 110-140°C.

[0028] Furthermore, the pH of the cyclization reaction material is adjusted to 4-6 and then a methylating agent is added, and the pH is optionally adjusted to 4.5-5.5.

[0029] Further, part or all of the low-boiling substances are evaporated from the cyclization reaction materials; optionally, the pH value is adjusted after part or all of the low-boiling substances are evaporated.

[0030] Further, the methylating agent includes dimethyl sulfate.

[0031] Further, the molar ratio of the N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the methylating agent is 1:0.5-10, optionally 1:1.0-1.5, optionally 1:1.2-1.5.

[0032] Furthermore, the methylation reaction temperature is 10-100°C, optionally 20-50°C.

[0033] Furthermore, an organic solvent is added to the methylation reaction, and the amount of the organic solvent added is optionally an amount sufficient to dissolve the intermediate product and / or raw material (it may not be added if the amount of solvent in the aforementioned reaction is sufficient); the organic solvent may include toluene, and the volume ratio of the strongly polar solvent to the organic solvent added is 1:0.1 to 10, and may be optionally 1:1 to 5 (e.g., 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5).

[0034] Furthermore, the pH value during the methylation reaction is controlled at 4 to 5.5.

[0035] Furthermore, water is added after the methylation reaction, the liquids are separated to obtain an organic phase, the solvent is removed, the temperature is lowered for crystallization, and saflufenacil is obtained.

[0036] Furthermore, the synthesis reaction adopts a one-pot method and there is no need to purify the intermediate product.

[0037] Beneficial Effects

[0038] (1) The solvent selected in the present invention can be used for a one-pot reaction, which can replace the scheme in the prior art in which each step of the reaction requires solvent switching and intermediate purification by filtering the discharged material. The reaction yield of the final product (safensulfuron) is high (>80%), the purity is good (>99%), and the purification step of the final product is simple. The reaction solvent selected in the present invention is relatively single and easy to recover, so that the reaction operation is simple, the product yield is improved, and the reaction is suitable for industrial scale-up production, and has broad application prospects.

[0039] (2) The reaction conditions of the present invention are mild, environmentally friendly, have high reaction yields, high product purity, and are suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] One or more embodiments are exemplarily described by the pictures in the accompanying drawings, and these exemplary descriptions do not constitute limitations on the embodiments. The special word "exemplary" here means "used as an example, embodiment or illustrative". Any embodiment described as "exemplary" here is not necessarily interpreted as being superior or better than other embodiments.

[0041] Figure 1 : It is the HPLC high performance liquid chromatography spectrogram product spectrogram of Example 1. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] In addition, in order to better illustrate the present invention, numerous specific details are provided in the specific embodiments below. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details. In some embodiments, raw materials, elements, methods, means, etc. well known to those skilled in the art are not described in detail, so as to highlight the main purpose of the present invention.

[0044] Unless explicitly stated otherwise, throughout the specification and claims, the term “comprise” or variations such as “include” or “comprising”, etc., will be understood to include the stated elements or components but not to exclude other elements or components.

[0045] In the following examples, all raw materials are commercially available. The purity of the target product was determined by liquid chromatography.

[0046] Example 1

[0047] 2 kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2 L of diethylene glycol dimethyl ether and 1.15 kg of ethyl chloroformate were added to a 20 L reactor, stirred, heated to 95 ° C and reacted for 3 hours. Samples were taken and the reaction was completed. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110°C, then add 4.22kg of 20% sodium ethanol ethanol solution dropwise, until the raw materials react completely, evaporate the low-boiling product (ethanol) in the reaction, add 3.9kg of 32% dilute sulfuric acid to adjust the pH to about 5, then add 0.97kg of dimethyl sulfate and 4L of toluene, heat to 40°C, add 10% liquid alkali to control the pH of the reaction liquid at 4-5, until the raw materials react completely, add 3L of water to obtain the toluene phase, desolventize and recover the toluene, after the remaining 2L of toluene, cool and crystallize, centrifuge to obtain 2.72kg of qualified product. The total yield is 87.9%, and the liquid phase normalization purity is 99.22% (such as Figure 1 ).

[0048] Example 2

[0049] 2 kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2 L of dipropylene glycol dimethyl ether and 0.8 kg of methyl chloroformate were added to a 20 L reactor, stirred, heated to 95 ° C and reacted for 3 hours. Samples were taken and the reaction was completed. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110°C, then drop 2.23kg of 30% sodium methoxide methanol solution, until the raw materials react completely, evaporate the low-boiling products (such as methanol and ethanol) in the reaction, add 3.9kg of 32% dilute sulfuric acid to adjust the pH to about 5, then add 0.97kg of dimethyl sulfate and 4L of toluene, heat to 40°C, drop 10% liquid alkali to control the pH of the reaction liquid at 4-5, until the raw materials react completely, add 3L of water to separate to obtain toluene phase, desolventize to recover toluene, and after 2L of toluene remains, cool and crystallize, centrifuge to obtain 2.66kg of qualified product. The total yield is 86.0%, and the liquid phase normalization purity is 99.55%.

[0050] Example 3

[0051] 2 kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2 L of polyethylene glycol 400 and 1.0 kg of ethyl chloroformate were added to a 20 L reactor, stirred, heated to 95°C and reacted for 3 hours. Samples were taken and the reaction was completed. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110°C, then add 4.22kg of 20% sodium ethoxide solution dropwise, until the raw materials react completely, evaporate the low-boiling products (such as ethanol) in the reaction, add 3.9kg of 32% dilute sulfuric acid to adjust the pH to about 5, then add 0.97kg of dimethyl sulfate and 4L of toluene, heat to 40°C, add 10% liquid alkali dropwise to control the pH of the reaction liquid at 4-5, until the raw materials react completely, add 3L of water to separate to obtain toluene phase, desolventize to recover toluene, and after 2L of toluene remains, cool and crystallize, centrifuge to obtain 2.62kg of qualified product. The total yield is 84.7%, and the liquid phase normalization purity is 99.25%.

[0052] Example 4

[0053] 2 kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2 L of N-methylpyrrolidone and 0.9 kg of ethyl chloroformate were added to a 20 L reactor, stirred, heated to 95°C and reacted for 3 hours. Samples were taken and the reaction was completed. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110°C, then add 4.22kg of 20% sodium ethoxide solution, until the raw materials react completely, evaporate the low-boiling products (such as ethanol) in the reaction, add 3.9kg of 32% dilute sulfuric acid to adjust the pH to about 5, then add 0.97kg of dimethyl sulfate and 4L of toluene, heat to 40°C, add 10% liquid alkali to control the pH of the reaction liquid at 4-5, until the raw materials react completely, add 3L of water to separate to obtain toluene phase, desolventize to recover toluene, and after 2L of toluene remains, cool and crystallize, centrifuge to obtain 2.47kg of qualified product. The total yield is 79.8%, and the liquid phase normalization purity is 99.65%.

[0054] Example 5-17

[0055] The difference from Example 1 is that the reaction solvent diethylene glycol dimethyl ether is replaced by diethylene glycol diethyl ether, diethylene glycol dipropyl ether, dipropylene glycol diethyl ether, dipropylene glycol dipropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dipropyl ether, propylene glycol dimethyl ether, propylene glycol diethyl ether, propylene glycol dipropyl ether, polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 800, respectively, and other conditions are the same as in Example 1, respectively used as Examples 5 to 17, and the reaction solvents, yields, and purities of Examples 5 to 17 are shown in Table 1.

[0056] Table 1. Reaction solvents used in Examples 5 to 17 and their reaction yields and purities

[0057] Solvents Reaction yield Liquid phase normalization purity Example 5 Diethylene glycol diethyl ether 85.3％ 99.45％ Example 6 Diethylene glycol dipropyl ether 85.6％ 99.30％ Example 7 Dipropylene glycol diethyl ether 86.0％ 99.40％ Example 8 Dipropylene glycol dipropyl ether 85.7％ 99.25％ Example 9 Ethylene glycol dimethyl ether 87.0％ 99.17％ Example 10 Ethylene glycol diethyl ether 86.5％ 99.55％ Embodiment 11 Ethylene glycol dipropyl ether 85.9％ 99.43％ Example 12 Propylene glycol dimethyl ether 86.2％ 99.32％ Embodiment 13 Propylene glycol diethyl ether 86.9％ 99.61％ Embodiment 14 Propylene glycol dipropyl ether 87.1％ 99.34％ Embodiment 15 Polyethylene glycol 200 84.0％ 99.25％ Example 16 Polyethylene glycol 400 85.1％ 99.44％ Embodiment 17 Polyethylene glycol 800 85.3％ 99.15％

[0058] Comparative Example 1

[0059] 2 kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2 L of DMF and 1.15 kg of ethyl chloroformate were added to a 20 L reactor, stirred, heated to 95°C and reacted for 3 hours. Samples were taken and the reaction was completed. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110°C, then add 4.22kg of 20% sodium ethoxide solution dropwise, until the raw materials react completely, evaporate the low-boiling products (such as ethanol) in the reaction, add 3.9kg of 32% dilute sulfuric acid to adjust the pH to about 5, then add 0.97kg of dimethyl sulfate and 4L of toluene, heat to 40°C, add 10% liquid alkali dropwise to control the pH of the reaction liquid at 4-5, until the raw materials react completely, add 3L of water to separate to obtain toluene phase, desolventize to recover toluene, and after 2L of toluene remains, cool and crystallize, centrifuge to obtain 1.55kg of qualified product. The total yield is 50.1%, and the liquid phase normalization purity is 97.75%.

[0060] In this comparative example, the product yield is relatively low. The inventors have found through continuous research that the use of DMF for one-pot process will result in more impurities being produced during the alkylation reaction, resulting in a low yield.

[0061] Comparative Example 2

[0062] Put 2kg of raw material (N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide), 2L of toluene and 0.8kg of methyl chloroformate into a 20L reactor, start stirring, heat to 95℃ and keep warm for 3 hours. Take a sample and the reaction is complete. Then add 1.4kg of 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester, start stirring and heat to 110℃, then add 4.22kg of 20% sodium ethanol solution dropwise, take a sample and control, and there is basically no reaction.

[0063] In this comparative example, when sodium ethoxide was added for cyclization reaction, there was basically no reaction. The inventors speculated through continuous research that it may be because toluene as a solvent is not polar enough, resulting in basically no reaction.

[0064] After discovering the above technical problems, the present invention has found through continuous research that by selecting a suitable strong polar solvent, the reaction can be carried out in a one-pot method, which can replace the phenomenon in the prior art that each step of the reaction requires solvent switching and filtering to remove the intermediate purification of the material. The reaction yield of the final product (safensulfuron) is high (>80%), and the purification step of the final product is simple. The reaction solvent selected by the present invention is relatively single and easy to recycle, so that the reaction operation is simple, the product yield is improved, and the present invention is suitable for industrial scale-up production and has broad application prospects.

[0065] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing saflufenacil, characterized in that: N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide is used as a raw material to react with chloroformate in a strong polar solvent, and then a base and 3-amino-4,4,4-trifluoro-2-butenoic acid ethyl ester are directly added to the reaction material to carry out a cyclization reaction, and the cyclization reaction material is subjected to a methylation reaction with a methylating agent to obtain saflufenacil.

2. The synthesis method according to claim 1, characterized in that The strong polar solvent includes one or more of N-methylpyrrolidone, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dipropyl ether, dipropylene glycol dimethyl ether, dipropylene glycol diethyl ether, dipropylene glycol dipropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dipropyl ether, propylene glycol dimethyl ether, propylene glycol diethyl ether, propylene glycol dipropyl ether, and polyethylene glycol 200-800; optionally, polyethylene glycol 200-800 includes one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800; And / or, the mass ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the strong polar solvent is 1:0.5-10, optionally 1:0.6-10, optionally 1:0.8-10, optionally 1:0.8-3.

3. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to chloroformate is 1:1.0-3.0, optionally 1:1.2-1.8; And / or, the chloroformate includes one or more of methyl chloroformate and ethyl chloroformate; And / or, in the reaction of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide with chloroformate, the reaction temperature is 15-130°C, optionally 80-110°C, optionally 90-100°C, optionally 95-100°C.

4. The synthesis method according to any one of claims 1 to 3, characterized in that: In the cyclization reaction, the base is a strong organic base; optionally, in the cyclization reaction, the base is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydrogen, sodium amide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; and / or, the molar ratio of N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the base is 1:1-10, optionally 1:1.6-2.5, optionally 1:2.0-2.5, optionally 1:1.9-2.2; And / or, the cyclization reaction temperature is 80-200°C, optionally 110-140°C.

5. The synthesis method according to any one of claims 1 to 4, characterized in that: The pH of the cyclization reaction material is adjusted to 4-6 and then a methylating agent is added, and the pH is optionally adjusted to 4.5-5.5; And / or, part or all of the low boiling substances are evaporated from the cyclization reaction materials; optionally, the pH value is adjusted after part or all of the low boiling substances are evaporated.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: Methylating agents include dimethyl sulfate; And / or, the molar ratio of the N-(2-chloro-4-fluoro-5-aminobenzoyl)-N'-isopropyl-N'-methylsulfonamide to the methylating agent is 1:0.5-10, optionally 1:1.0-1.5, optionally 1:1.2-1.

5.

7. The synthesis method according to any one of claims 1 to 6, characterized in that: The methylation reaction temperature is 10-100°C, optionally 20-50°C.

8. The synthesis method according to any one of claims 1 to 7, characterized in that: In the methylation reaction, an organic solvent is also added, and the amount of the organic solvent added is optionally an amount that dissolves the intermediate product and / or the raw material; the organic solvent optionally includes toluene, and the volume ratio of the strongly polar solvent to the organic solvent added is 1:0.1 to 10, and optionally 1:1 to 5; And / or, the pH value during the methylation reaction is controlled at 4 to 5.

5.

9. The synthesis method according to any one of claims 1 to 8, characterized in that: After the methylation reaction, water is added, the liquids are separated to obtain an organic phase, the solvent is removed, the temperature is lowered for crystallization, and saflufenacil is obtained.

10. The synthesis method according to any one of claims 1 to 9, characterized in that: The synthesis reaction adopts a one-pot method and there is no need to purify the intermediate products.

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